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12 Loren, 1., Alumets, J., Hakanson, R. and Sandier, F. (1979) Cell Tissue Res. 200, 179-186 13 Loren, 1., Emson, P. C., Fahrenkrug, J., Bjorklund, A., Alamets, J., Hakanson, J. and Sundler, F. (1979)Neuroscience 4, 1953-1976 14 Magistretti, P. J., Monison, J. H., Shoemaker, W. J., Sapin, V. and Bloom, F. E. (1981) Proc. Natl Acad, Sci. U.S.A. 78, 6535-6539 15 Molliver, M. E., Grzanna, R., Lidov, H. G. W., Monison, J. H. and Olschowka, J. A. (1982)

Cytochemical Methods in Neuroanatomy (Chan-Palay, V. and Palay, S. L., eds), pp. 255-277, Alan R. Liss, New York 16 Morrison, J. H., Benoit, R., Magistretti, P. J. and Bloom, F. E. Brain Res. (in press) 17 Monison, J. H., Foote, S. L., Molliver, M. E., Bloom, F. E. and Lidov, H. G. W. (1982) Proc. Natl Acad. Sci. U.S.A. 79, 2401-2405 18 Monison, J. H., Foote, S. L., O'Connor, D. and

Bloom, F. E. (1982)Brain Res. Bull. 9, 309-319 19 Monison, J. H., Grzanna, R., Coyle, J. T. and Molliver, M. E. (1978)J. Comp. Neurol. 181, 17-40 20 Monison, J. H., MoUiver,M. E., Grzanna, R. and Coyle, J. T. (1979) Brain Res. Bull. 4, 849--857 21 Monison, J. H., Molliver, M, E., Grzanna, R. and Coyle, J. T. ( 1981) Neueoscience 6, 139-158 22 Peters, A. and Kirnerer, L. M. (1981)J. Neurocytol. 10, 921-946 23 Peters, A., Miller, M. and Kimerer, L. M. (1983) Neuroscience (in press) 24 Phillis, J. W. and Kirkpatriek, J. R. (1980) Can.J. Physiol. PharrnacoL 58,612~23 25 Pittman, Q. J. and Siggins, G. R. (1981) Brain Res. 221,402-408 26 Quach, T. T., Rose, C. and Schwartz, J.-C. (1978)J. Neurochem. 30, 1335-1341 27 Quik, M., Iversen, L. L. and Bloom, S. R. (1978)

Undernutrition and brain development Ambrish J. Patel Undernutrition has many medical and social consequences, o f which those arising from the vulnerability of the immature brain to metabolic imbalance are o f particular importance. Originally, animal models were expected to provide an adequate means o f studying these effects, in the belief that the major variable was food intake. Systematic investigation o f this problem began late in the nineteenth century with the work o f Donaldson and his colleagues (in particular Sugita) working at the Wistar Institute 8. Their work indicated the importance o f the timing o f the nutritional insult in addition to the degree o f deprivation. Subsequently, an attractive hypothesis has evolved, namely that the type o f vulnerability to an insult is closely related to the timetable o f developmental events at the time o f the insult (see Refs 1, 5). Here, 1 shall refer to the various types o f nutritional deprivation as undernutrition, although it is possible that they may not produce precisely the same result. Furthermore, it has now become evident that undernutrition is associated with social and psychological factors, which in themselves affect brain development not only in man but also in experimental animals. With these qualifications, the present article reviews physical changes resulting from undernutrition during major phases o f brain development in experimental animals. Growth Rats whose development is restricted by undernutrition during the suckling period never catch up with control rats, either in body or in brain growth, even if they are rehabilitated after weaning. Body growth is more severely affected than that o f the brain, and this has been interpreted as a sparing effect on the brain. The reduction in brain size is not uniform throughout the brain, but certain regions, most notably the cerebellum, are substantially more affected than the rest tT. Growth of the brain, like that of other organs, is related to the acquisition and differentiation of cells, and neonatal undernutrition is found to affect both o f these processes in the rat.

Cell proliferation The total number of cells (including

neurons and glia) in rat brain is approximately 420 million 1~'17. For obvious reasons they have never been counted but are estimated from the D N A content. The h u m a n brain weighs about 700 times that of the rat, and it contains approximately 250 x 10 a cells. Cell formation occurs over a relatively restricted period, up to about 3 weeks postnatally in the rat and probably up to 2 years in man. A large proportion of brain cells (approximately 70%) are formed after birth in both these species, and in certain parts o f the forebrain, such as the hippocampus and the olfactory bulbs, and in the cerebellum, a significant number of these postnataUy acquired cells are neurons. Cell proliferation occurs largely in circumscribed sites. Characterization of these sites in the various parts of the brain, in terms of the classes of cells they gener-

Biochem. Pharmacol. 27, 2209-2213 28 Ungerstedt, U. (1971)Acta Physiol. Scand. Suppl. 367, 1-48 29 Weber, E., Evans, C. J., Samuelsson, S. J. and Barchas, J. D. (1981)Science 214, 1248-1251 30 Benoit,R., Bohlen, P., Ling, N., Briskin,A., Esch, F., Brazeau, P., Ying, S. Y. and Gttillemin, R. (1982) Proc. NatlAcad. Sci. U.S.A. 79, 917-921 31 Benoil, R., Ling, N., Bakhit, C., Morrison,J. H., Alford, B. and Guillemin, R. (1982) Endocrinology 111, 2149-2151

John H. Morrisonand PierreJ. Magistrettiare.from the Arthur V. Davis Center for Behavioral Neurobiology, The Sulk Institute, La Jolla, CA 92037, U.S.A. Pierre J. Magistretti is now at the Depanement de Pharrnacologie, Centre Medical Universitaire, Geneva, Switzerland. ate, permits differential analysis of the proliferation kinetics of precursor cells. These are, for example, either predominantly neuronal, as in the cerebellar external granular layer, or they are glial, as in the forebrain lateral ventricular subependymal layer. Undernutrition during the fLrst 3 weeks of postnatal life results in a moderate (approximately 15%) depression of cell numbers in the rat brain. In contrast, the rate of D N A synthesis in the brains of these rats is very severely reduced, and at its nadir is only 2 0 - 3 0 % o f the control values ~7. These puzzling results ultimately proved to be of great value in understanding the mechanisms underlying disturbed cell proliferation in undernutrition. Further studies, carried out in collaboration with Paul Lewis (Royal Postgraduate Medical School, London), showed that the discrepancy between the effects of undernutrition on the rates of cell acquisition and on those of D N A synthesis could be largely accounted for by a disproportionately greater prolongation of the D N A synthesis (S) phase of the cell cycle than of the duration of the cycle of generation ~°. This relatively small effect of the treatment on cell-cycle time, in spite of the prolongation of the DNA-synthesis phase, was a consequence of a severe curtailment o f the length of the Gl-phase of the cell cycle. The derangement of the generation cycle in undernutrition has now been detected in the germinal sites of the forebrain, cerebellum and hippocampus and is unique to the developing brain. It is not detectable in the residual subependymal layer in food-deprived young adult rats, where both the S-phase and the overall cell-cycle time are more or less proportionately prolonged ~1. Similarly, with other adult tissues containing rapidly proliferating ceils, food deprivation results in a marked lengthening of the cell-cycle time including both the S-phase and the G1phase (see Ref. 1 ). It seems that in the

(~ 1983.ElsevierSciencePublishersB.V . Amsterdam 0378- 5~12/83/$01(X~

152 developing brain a regulatory mechanism exists to prevent a fall in cell-acquisition rate even in the face of a reduced rate of DNA synthesis. However, such a compensatory mechanism may have adverse consequences, because of the severe curtailment of the length of the Gt-phase. It has been shown that events occurring during a limited period of the Gt-phase are critical in terms of the full expression of the normal differentiated functions of some cells22. Cellular composition Quantitative estimates of cellular composition have to be made on a very small part of the tissue, and the results, as well as not being representative of the organ as a whole, can only provide estimates of cell density or ratios of the numbers of one cell type to another. Thus, it is not suprising that sometimes data from one laboratory do not completely agree with those of another. Nevertheless some consistent patterns do emerge, showing lasting changes in the cellular composition of the brain of the undernourished rat (see Ref. 1). The 'birthdays' of many different nervecell populations, as determined in the mammalian brain by [3H]thymidine autoradiography, are fixed, indicating that the chronology of neurogenesis follows a rigid timetable 16. This largely explains why one neuronal cell type is much more affected than another in undernourished rats. In the cerebellum, there is a reduction in the number of postnatally formed granule and basket cells, but no changehas been detected in the number of perinatally formed Golgi neurons. The results concerning any reduction in the number of Purkinje" cells, which are formed prenatally, are controversial: some investigators report that there is a deficit in the number of these cells even after rehabilitation, whereas other reports imply that undernutfition has no effect of Purkinje-cell numbers (see Refs 1, 2, 3, 12). These apparent reductions, taken together with the reported selective loss of nerve cells from the deeper layers of the cerebral cortex in undernourished animals, may suggest that a normal food supply is required not only for the formation of cells, but also for their maintenance. Furthermore, it would appear that undernutrition affects glial cells more severely both in their formation and migration - glia are acquired at a relatively later age than neurons. In the cerebellum, there is a general tendency for all the different types of neuroglial cells to decrease in undernutrition, with a reduction in glial spaces in the molecular layer; again, in the forebrain a lasting deficit in glial-cell numbers, including mature oligodendrocytes, has been reported even after postweaning rehabilitation ~,9.

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Dendritic arborization and associated synaptogenesis

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However, such experimentai recovery did not occur without very active encouragement, so that its promotion by feeding a proper diet and adequate enviro~-~mental stimulation is an urgent and imlx)nant matter.

Early attempts to quantitate these structural changes have been very few and methodologically unsatisfactory, but they do suggest substantial reduction of both dendritic arborization and synaptic number during the period of infant undernutrition Manifestation of biochemical indices (see Ref. 1). Most recent studies, done at During maturation, the metabolic pattern Birmingham University by Martin Berry of undifferentiated cells is altered in such a and his associates, on dendritic-network way as to result in the development of a analysis of Purkinje cells have conftrmed unique co-ordination of the different the reduction in dendritic complexity t2. In metabolic pathways characteristic of the undernutrition the significant decrease in differentiated adult cells. We have used two overall dendritic length, with a reduction in such biochemical markers of brain maturaboth numbers and length of segments, is tion. These are: the conversion of glucose related to the decrease in granule-cell hum- carbon into amino acids, as an indicator of hers. On rehabilitation some recovery the fate of labelled glucose; and the including dendritic remodelling does occur, glutamine to glutamate specific radioactivalthough the size and morphology of the ity ratio after the administration of labelled dendritic network is not completely amino acids or fatty acids, as an index of the restored. In spite of these findings, other "appearance of signs of the metabolic comobservations have indicated that undernutri- partmentation of glutamate. Both these tion has relatively little effect on the biochemical indices have been found to be development of neuronal circuits in the sensitive indicators of the progress of brain cerebellum (see Ref. 1). There is little development under various experimental alteration in the tinting of the change-over conditions l'~ Undernutrition during defrom the initial axosomatic to the final velopment results in a decrease in the axodendritic synaptic contacts between conversion of glucose carbon into amino climbing fibres and Purkinje cells; and acids in the brain. This was found to be a although the length of the granule-cell composite effect resulting from (a)a depresdendrites is reduced, the overall develop- sion in the concentration of amino acids, ment of cerebellar glomeruli, where the which serve as a 'trap' for glucose carbon mossy-fibre input is transmitted to the entering the tricarboxylic acid cycle; (b) an granule cells, is not impaired. Recently, increase in the blood concentration of using modern stereological methods, John ketone bodies, which are important alternaDobbing and his collaborators at Manches- tive substrates for oxidation; and (c) a ter University investigated the important decrease in the flux of glucose utilization in question of whether a deficit in synaptic the brain. Similarly, another biochemical number in undernourished rats is recover- index of brain maturation, the development able, and the answer is that it appears to be. of metabolic compartmentation of glutaBoth in the frontal cortex and in the cerebel- mate, was severely retarded in undemular granular layer the numbers of synapses trition is. On rehabilitation, both indices of per neuron are restored to normal by brain maturation showed complete restorarehabilitating 30-day-old undernourished tion to normal, indicating that undemutrirats for 160 days 2,3. It is interesting to note tion does not inflict irreversible damage on that in normal rats the synaptic number at least these underlying biochemical prodecreases in the frontal cortex and increases cesses of cell differentiation. in the cerebellar granular layer between 30 and 160 days, and the 'catch-up' in rehabili- Neurotransmitter enzymes The influence of undernutrition on the tated animals was mainly due to relatively less decrease in synaptic number in the development of neurotransmitter systems frontal cortex and more increase in the can be followed by estimating the concencerebellum. These results suggest a mas- tration and turnover of putative transmitter sive change in synaptogenesis continuing substances, the activity of enzymes critical well beyond the normally assumed short in the synthesis of transmitters and the period of early brain development, which is kinetics of neurotransmitter receptors. about 4 weeks after birth in the rat. Similar Neurotransmitter enzymes are usually marked changes in synaptic number in the enriched in presynaptic nerve endings, and visual cortex and in dendritic arborization thus may be considered as good markers of in pyramidal and Purkinje cells have been the differentiation of these structures. Our observed in adult animals exposed to con- studies on the effects of undernutrition on ditions of varying environmental stimula- the regional development of choline acetyltionl~-2L These changes are an indication transferase and glutamate decarboxylase of the structural plasticity of the brain. highlight a number of points which may

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have a bearing on the functional consequences of a metabolic insult occurring during brain ontogenesis TM. Undernutrition results in a marked retardation of the development of both the acetylcholine and 7aminobutyric acid neurotransmitter systems in all the eight brain parts studied. However, the effect diminishes with age even during the period of nutritional deprivation, and in most regions the enzyme activities were restored to normal after rehabilitation. Furthermore by day 21 in controls the two enzyme activities in the different brain regions manifested a significant inverse correlation. This appeared in the undernourished rats only after rehabilitation. Therefore undernutrition seems to lead to distortions rather than synchronized shifts in the relative development of at least these two transmitter systems.

Monoamine neurotransmitters Undernutrition also causes a marked change in the development of the catecholaminergic systems; however, findings have been somewhat equivocal (for references, see Refs. 1, 6). Some investigators have reported a reversible retardation in the developmental increase of catecholamine concentrations, others have observed a trend for increased noradrenaline concentrations, while yet others have found normal concentrations but decreased total amounts of brain catecholamines. It was also claimed that the noradrenaline turnover rate is decreased in undernutrition; however, this was accompanied by an increase in one study and a decrease in another of the activities of tyrosine hydroxylase in the brain. 5-Hydroxytryptamine (5-HT) systems have been implicated in the changes in emotional behaviour, which seems to be altered by early undernutrition',e'. It has been reported that the rate of 5-HT and catecholamine synthesis is increased after a rise in the serum concentration of tryptophan and tyrosine, respectively, and decreased when the concentration of amino acids which compete for the career transporting tryptophan or tyrosine from blood to brain is substantially elevated 24. Thus, nutritional factors may influence the central metabolism of monoamines by affecting the availability of their precursors to the brain. However, tryptophan is the only amino acid which is specifically bound to albumin in the blood, and both in laboratory animals and in man the rate of brain 5-HT synthesis correlates with the concentration of free rather than of total tryptophan in the blood s. The levels of 5-HT and its principal metabolite 5-hydroxyindoleacetic acid are elevated in the brain of the young of protein-deficient mother rats. There may be

accelerated 5-HT synthesis as a result of the elevation in the plasma concentration of free tryptophan, in turn associated with a reduction in serum albumin content and also an increase in circulating free fatty acids, which compete with tryptophan for the albumin-binding sites ~4. It is also claimed that 5-HT turnover is selectively increased in the hippocampus of rehabilitated rats. In protein-deficient rats, electrical foot-shock results in a significant depletion of 5-HT and noradrenaline in the midbrain and the pons-medulla, an effect not seen in adequately fed animals or in normal rats switched in adulthood to low protein diet. However, some of these changes might have been mediated by nonnutritional factors such as hormonal imbalance during development (see Ref. 1). Probably of particular relevance is the alteration of corticosteroids secretion in undernutrition. The concentration of free corticosteroids in the blood is high in undernourished infant rats, and this may influence monoamine metabolism by altering the activities of enzymes involved in the synthesis of these neurotransmitters in the developing brain ~3.

Functional implications

tional alterations induced by early undernutrition are permanent. In fact, it has proved difficult to demonstrate any residual effects on behaviour of children in affluent homes, who happen to have been severely undernourished in childhood due to paediatric diseases such as cystic fibrosis or pyloric stenosis. Similarly, it has been reported that in a group of Korean adoptees a total change to a 'stimulating' environment can prevent the expected low intelligence and poor school performance previously found among undernourished childrenz~. However, this does not mean that the neuropathology of developmental undernutrition described here is of no importance, instead it testifies to the plasticity and great capacity of the central nervous system for compensation. There can be no doubt that most of the effects of early undernutrition are reversible, and intellectual performance can be influenced by varying conditions of environmental stimulation, the latter may be conceived of as exerting their effects by altering nerve-cell growth and synaptogenesis 1~2'.

Conclusion Undernutrition in the developing rat causes characteristic distortions in the generation cycle of replicating neuronal or glial cells. There is a permanent deficit in total cell number and a distortion of the cellular composition. The manifestations of structural and biochemical development of the brain are retarded in undemutrition. It is probably more relevant that distortions in the normal co-ordinated pattern of transmitter systems are detectable. In view of the importance of the chronology of development in relation to the ultimate integration of the central nervous system, such distortions, rather than lasting deficits and lesions, are more important in determining the effects on brain function. Nutritional rehabilitation after weaning can however correct, to some extent, many of the physical alterations, and synaptogenesis can also be modified by varying conditions of environmental stimulation. This shows that the plasticity of the central nervous system extends well beyond the relatively short period of early brain development. Plans for positive rehabilitation of undernourished children should take full advantage of this fact.

There is no doubt that undernutrition in developing experimental animals (which is relatively less severe than commonly seen in starving children) can affect the structural and biochemical maturation of the brain. Some, but by no means all, manifestations of brain development show retardation rather than permanent alterations, since nutritional rehabilitation after weaning is able to correct many of the physical changes. However, because of the importance of programmed chronology in development in relation to the ultimate integrative organization of the central nervous system, the observed distortions in the normal pattern of brain development are more important in determining effects on brain functions. Along with the physical alterations, during undernutrition brain performance is undoubtedly impaired; however, the situation after nutritional rehabilitation is less clear. Careful analysis has indicated that there are always many nonnutritional factors of unknown mode of action, including the maternal-infant relationship, motivation and emotionality, which contribute significantly to the apparently impaired performance observed in the Acknowledgements The author is indebted to Dr R. Bakizs for his undernourished animals 7. Evidence from human studies points in advice and encouragement. the same direction4,2°. Human infants who Reading list have suffered a bout of undernutrition in 1 Bahizs,R.. Lewis, P. D. and Patel. A. J. (1979)in early life show impairment in mental Human Growth (Falkner, F. and Tanner, J. N., development. Until recently, it was eds). Vol. 3. pp. 415-480, Plenum, New York believed that both the structural and func2 Bedi, K. S., Thomas, Y. M., Davies. C. A. and

154 Dobbing, J. (1980)J. Comp. Neurol. 193, 49--56 3 Bedi, K. S., Hall, R., Davies, C. A. and Dobbing, J. (1980)J. Comp. Neurol. 193, 863-87O 4 Cravioto, J. and DiLicardie, E. R. (1979) in Human Growth (Falkner, F. and Tanner, J. N, eds), Vol. 3, pp. 481-511, Plenum, New York 5 Dobbing, J. (1974) in Scientific Foundations of Pediatrics (Davies, J. A. and Dobbing, J., eds), pp. 565-577, Heinemann, London 6 Dodge, P. R., Prensky, A. L. and Feigin, R D. (1975) Nutrition and the Developing Nervous System, C. V. Mosby, St Louis 7 Frankova, S. (1980) in Multidisciplinary Approach to Brain Development (De Benedetta, C., Balazs, R., Gombos, G. and Porcellati, G., eds), pp. 359-371. Elsevier, Amsterdam 8 Gillman, P. K., Bartlett, J. R., Bridges, P. K., Hunt, A., Patel, A. J., Kantamaneni, B. D. and Curzon, G. (1981)J. Neurochem. 37,410--417 9 Lai, M., Lewis, P. D. and Patel, A. J. (1981)

J. Uomp. Neurol. 193,965--972 10 Lewis, P. D., Bal~lzs,R., Patel, A. J. and Johnson, A. L (1975)Brain Res. 83,235-247 I1 Lewis, P. D., Patel, A. J. and Balfizs, R. (1977) Brain Res. 138, 511-519 12 McConnell, P. and Berry, M. (1981) J. Comp. Neurol. 200, 463-479 13 McEwen, B. S. and Micco, D. J. (1980) in Hormones and the Brain (De Wied, D. and van Keep, P. A.. eds), pp. 11-28, MTP Press, Lancester 14 Miller, M. and Resnick, O. (1980)Exp. NeuroL 67,298--314 15 Patel, A. J. and Balhzs, R. (1975) in Metabolic Compartmentation and Neurotransmission, Relation to Brain Structure and Function (Bed, S, Clarke, D. D. and Schneider, D., eds), pp. 363--383, Plenum, New York 16 Patet, A. J. and Lewis, P. D. (1982) in Mechanis'n~ of Actions of Neurotoxic Substances (Prasad, K. N. and Vernadakis, A., eds), pp. 18t-218, Raven, New York

Problems wRh the past Historical Aspects of the Neurosciences edited by F. Clifford R o s e a n d W. F. B y n u m , R a v e n Press, 1982. $ 7 8 . 8 8 (xix + 5 3 7 p a g e s ) I S B N 0 8 9 0 0 4 661 1 This book consists o f 46 essays on the history of the neurosciences in honour of Macdonald Critchley's eightieth year. They come from a select band of professional historians o f medicine and from a larger group of colleagues and pupils in medical practice, writing as amateur medical historians. Not surprisingly, the amateurs are accurate and informative on the medicine of the nineteenth century when the foundations were being laid o f the knowledge they have used in their professional lives. Again, it is not surprising that the professional historians come into their own in the history o f the eighteenth century and earlier, when little medical knowledge as opposed to understanding of the development o f ideas and the history o f the times is required. Difficulties arise when the amateurs step outside theft areas of expertise, and sometimes their knowledge of even nineteenth-century medicine is remarkably narrow. For example, a Dr Hughes Bennett is described as the son of the m a n who first r e c o m m e n d e d cod-liver oil. In fact, the m e m o r y of Hughes Bennett p~re is kept green in Edinburgh by a benefaction, and his real achievements were the discovery of leukaemia, the introduction of histology to the medical curriculum and his battle to prove to this colleagues in the Royal Infirmary that bleeding in pneumonia produced a considerable increase in death rate. Although his statistics were reliable, the

only result was that his colleagues did not elect him to the Chair of Medicine. In a rather thin biography of Victor Horsley, Irving S. Cooper makes nothing of the work of Clarke of the Clarke-Horsley stereotaxic machine. One only has to read the supplement to the Bulletin o f the J o h n s H o p k i n s Hospital (t 921 ) to be convinced that it was Clarke who was the mechanical genius. W h e n the amateurs stray into the field of the professionals in order to describe the early history of their subject, trouble arises. Mark Gawel's account of the early history of the study of the circulation from Ibnan-Nafis to Servetus, Fabricius and Harvey is full o f slap-dash statements and inaccuracies which are happily absent when he soberly discusses the twentieth-century work on cerebral circulation. A m o n g the professional historians, Kenneth Dewhurst stands out for his defence of Willis from the charge of exploiting his dependants and junior colleagues by quoting Lower, who speaks well of Willis both before and after his death. While accounts of obscure syndromes can be fascinating, obscure neurologists are very difficult to rehabilitate. Not even piety

17 Patel, A. J. Balfizs,R. and Johrlson, A [. (b973 'J. Neurochem. 20, 1151-1165 18 Patel, A J., Det Vecchio, M. m~dAtkinson, D i (1978) Dev. Neurosci. I, 41-53 19 Pysh. J. J. and Weis, G. M (l~79)Science 2o0, 23O-232 20 Richardson, S. A., Birch. l-J ~3 and Hertzig, M. E. (1973)Ann. J. Men. Defic 77. 6234~32 21 Uylings, H. B. M., Kuypers, K and Velttnan, W. A. M. (1978)Prog. Brain Res. 48,261--272 22 Vonderhaar, B. K. and Topper, Y. J. 11974) J. Cell Biol. 63,707-712 23 Winick, M., Meyes, K. K. and Harris, R. C (1975)Science 190, 1173-117s 24 Wurtman, R. J. and Fernstrom..I, D. (1975)Am. J. CTin. Nutr. 28,638~M-7

Ambrish, J. Patel is Senior Scientific 34ember of the Medical Research Council Developmental Neurobiology Unit, Institute of Neurology, London WCIN 2NS, U.K to King's College Hospital can help me feel that Bentley Todd was more than a competent teacher and very dull man, and Gilles de la Tourette remains unattractive in spite of his biographer's best efforts. On the other hand, the accounts of the history of migraine, narcolepsy, syringomyelia and even the syndrome of Capgras are very entertaining. One of the best biographies is that of the last of the giants of neurology, Gordon Holmes. Parsons Smith uses a variety of sources and personal recollections to paint a worthy picture of the m a n and his work, and stresses the devotion of his pupils, 1 remember when he was president o f the Association of the British Neurologists in 1945, he made brilliantly apposite comments on each of the papers given. Of the histories of specialities, by far the most interesting is that by Bull on neuroradiology - full of information very difficult to find elsewhere. T h o u g h the range of subjects tackled no doubt reflects the range of Macdonald Critchley, s interests, the treatment they get varies widely in length and in depth. One could perhaps wish that the editors had been able to be a little more selective or had disciplined more closely their rather individualistic crew. D. W H I T r E ~ E Formerly Wavnflete Professor of Physiology, Department of Experimental Psychology, Oxford University, South Parks Road, Oxford OXI 3UD, U.K.

East n'.sets West at the synapse Pharmacology of Ganglionic Transmission edited by D. A. K h a r k e v i c h , SpringerVerlag, 1 980. $ 1 3 7 . 2 0 (xiii + 531 pages) ISBN 3 540 09592 6 It was indeed a pleasure to receive this vol-

u m e and discover that it was truly a scholarly book devoted to the subject in its title. Often, such edited volumes and serials carry an attractive generalized title to c o v e r a collection of loosely related, highly focused research papers. Hence, these articles tend to have only immediate value